Project Summary/Abstract GABAergic interneurons are critical for the maintenance of proper levels of cortical excitability. However, very little is known about the mechanisms involved in the control of their activity. Specifically, there is a critical need to understand the formation and maintenance of inhibitory synaptic inputs onto interneurons. Our long-term goal is to gain a better understanding of the molecular mechanisms involved in the control of inhibitory interneuron activity to allow for manipulation of synaptic inhibition in neuropsychiatric disorders where cortical activity is disrupted. The overall goal is to determine the role of Neuroligin 2 (Nlgn2) in the regulation of this inhibition and to better understand how loss of Nlgn2 alters the activity of the inhibitory interneurons and leads to disease. The central hypothesis is that Nlgn2 plays an essential role in the regulation of inhibition onto GABAergic interneurons and loss of Nlgn2 in interneurons leads to functional consequences on cortical activity that may result in neuropsychiatric symptoms. Loss of Nlgn2 in somatostatin positive (Sst+) interneurons results in a decrease in the frequency and amplitude of synaptic inhibitory inputs onto those cells. Aim one will combine classical synaptic physiology and pharmacology with input-specific optogenetics to identify the synaptic mechanisms that lead to alterations in inhibitory inputs onto Sst+ interneurons. Aim two will use in vivo Ca2+ imaging and electroencephalography (EEG) recordings to determine the functional consequences of loss of Nlgn2 in Sst+ interneurons on both cellular activity and overall cortical activity, respectively. These important questions have yet to be addressed due to critical barriers including the inability to specifically manipulate inhibitory synapses onto interneurons and the inability to directly test and manipulate the connections between subtypes of interneurons in slice electrophysiology. This proposal overcomes these barriers due to a novel approach that utilizes viral genetics, Cre recombinase, and FlpO recombinase, and the specific manipulation of Nlgn2, a post-synaptic protein found exclusively at inhibitory synapses. The proposed research is expected to elucidate the molecular mechanisms involved specifically in the regulation of cortical interneuron activity. This contribution will be significant because it will allow for the manipulation of interneuron activity to alter levels of cortical inhibition, serving as a novel therapeutic target therapy for neuropsychiatric diseases in the future.